title: Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.
abstract: BACKGROUND
  Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening.
  
  
  RESULTS
  The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression.
  
  
  CONCLUSIONS
  Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. j.c.herkert@medgen.umcg.nl
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Herkert
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Maria J W
authors.initials: MJ
authors.lastname: Olderode-Berends
authors.forename: Hermine E
authors.initials: HE
authors.lastname: Veenstra-Knol
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.forename: Heleen M
authors.initials: HM
authors.lastname: van der Klift
authors.forename: Rene
authors.initials: R
authors.lastname: Scheenstra
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
authors.forename: Arend
authors.initials: A
authors.lastname: Karrenbeld
authors.forename: Frans T M
authors.initials: FT
authors.lastname: Peters
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D020137:Base Pair Mismatch; D002648:Child; D002675:Child, Preschool; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007414:Intestinal Neoplasms / Q000235:genetics*; D044483:Intestinal Polyposis / Q000235:genetics*; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D000070976:Mismatch Repair Endonuclease PMS2; D009154:Mutation; D013577:Syndrome
chemical_list: D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes